Measles Virotherapy and radiovirotherapy in the Treatment of recurrent gliomas

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，在美国每年18，500例原发性脑肿瘤病例中占大多数。尽管采用了多种治疗方法，但其预后仍很差，中位生存期为12-15个月。迫切需要新的治疗剂。我们的小组是第一个证明工程麻疹病毒（MV）株对神经胶质瘤具有显着的抗肿瘤活性。它们的肿瘤特异性是由于MV受体CD 46在胶质瘤细胞中的大量表达。病毒进入肿瘤细胞后，引起与邻近细胞的膜融合、合胞体形成和死亡。此外，我们已经将这种方法转化为在复发性GBM患者中进行的麻疹病毒衍生物产生人类癌胚抗原MV-CEA（添加CEA以促进病毒监测）的首次人类临床试验。我们现在假设，通过引入治疗性转基因并抑制先天免疫反应，我们可以进一步增强麻疹病毒疗法在胶质瘤中的抗肿瘤活性。我们建议通过测试三种新方法在胶质瘤治疗中的翻译潜力来实现这一目标;一种不同的麻疹病毒株MV-NIS，其编码钠碘同向转运体（NIS）基因，从而允许体内病毒分布的成像;通过利用NIS作为治疗性转基因并应用β和γ发射体131 I来增强MV-NIS的溶瘤作用。（放射病毒疗法）;以及将麻疹病毒衍生物与环磷酰胺组合，环磷酰胺是一种已显示抑制抗病毒先天性和适应性免疫并增加肿瘤中病毒增殖的药剂。因此，本资助提案具有以下具体目标：1）测试MV-NIS在GBM系和异种移植物中的放射病毒治疗的功效，将其与MV-CEA进行比较，并研究抗肿瘤活性的机制; 2）通过将麻疹衍生物与环磷酰胺（CPA）组合来进一步提高麻疹病毒治疗或放射病毒治疗的效力，并在此背景下优化CPA的剂量和时间表; 3）在两种麻疹复制许可动物模型（IfnarkoCD 46 Ge转基因小鼠和恒河猴）中研究病毒的生物分布、与免疫系统的相互作用以及颅内给药后的安全性。 公共卫生相关性：与其他更常见的癌症相比，恶性胶质瘤除了显著降低预期寿命外，还造成不成比例的发病率。在临床前模型中，麻疹疫苗株对神经胶质瘤具有有效的抗肿瘤活性，并与现有疗法具有协同作用。本申请旨在研究麻疹疫苗株作为新型抗肿瘤药物在复发性胶质瘤治疗中的最佳使用策略。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, accounting for most of 18,500 primary brain tumor cases each year in the US. Prognosis is dismal with a median survival of 12-15 mo, despite use of multimodality treatment. Novel therapeutic agents are urgently needed. Our group was the first to demonstrate that engineered measles virus (MV) strains have significant antitumor activity against gliomas. Their tumor specificity is due to abundant expression of the MV receptor CD46 in glioma cells. The virus upon entry in the tumor cells, causes membrane fusion with neighboring cells, syncytia formation and death. In addition, we have translated this approach into the first human clinical trial of a measles virus derivative producing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate viral monitoring) in recurrent GBM patients. We now hypothesize that by introducing a therapeutic transgene and suppressing the innate immune response, we can further augment the antitumor activity of measles virotherapy in gliomas. We propose to accomplish this by testing the translational potential of three novel approaches in glioma treatment; a different measles virus strain, MV-NIS, which encodes the sodium iodine symporter (NIS) gene, thus allowing imaging of viral distribution in vivo; enhancing MV-NIS oncolysis, by exploiting NIS as therapeutic transgene with application of the beta and gamma emitter 131I (radiovirotherapy); and combining measles virus derivatives with cyclophosphamide, an agent that has been shown to suppress anti-viral innate and adaptive immunity, and increase viral proliferation in tumors. This grant proposal has therefore the following specific aims: 1) to test the efficacy of radiovirotherapy with MV-NIS in GBM lines and xenografts, compare it with MV-CEA and investigate the mechanism of antitumor activity; 2) to further increase the potency of measles virotherapy or radiovirotherapy by combining measles derivatives with cyclophosphamide (CPA), and optimize CPA's dose and schedule in this context; 3) to study viral biodistribution, interaction with the immune system and safety following intracranial administration, in two measles replication permissive animal models, Ifnarko CD46 Ge transgenic mice and Rhesus macaques. PUBLIC HEALTH RELEVANCE: Compared to other more common cancers malignant gliomas are responsible for a disproportionate amount of morbidity, in addition to significant reduction in life expectancy. In preclinical models, measles vaccine strains have potent antitumor activity against gliomas and demonstrate synergy with existing therapies. This application proposes to investigate strategies optimizing the use of measles vaccine strains as novel antitumor agents in the treatment of recurrent gliomas.